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Coordination-driven self-assembly provides unique opportunities to design and prepare ordered arrays of molecules and clusters, and has led to significant progress in the construction of metal-organic assemblies with potentially exploitable functions, from ion exchange to gas storage to separations to catalysis. [1, 2] Of particular interest to us are elegant works on coordination-linked porphyrin arrays that demonstrate the feasibility of constructing a large family of meso-metalloporphyrin cycles and boxes based on complementary coordination interactions between coordinatively unsaturated central metal atoms and coordinating sidearms.[3] This assembling process is especially effective for the construction of discrete cyclic arrays, in that appropriately designed components are almost automatically self-assembled to form large arrays, thus providing an associated entropic advantage.[3c] However, such a direct approach has thus far received less attention in other supramolecular systems. [4,5] Metallosalen-based architectures (salen = N,N'-ethylenebis(salicylideneaminato)) have diverse potential applications in catalysis and separations, [6, 7] which motivated us to examine the self-assembly of enantiopure complementary metallosalen complexes through coordination, with the aim of generating well-defined enzyme-like chiral cavities and functionalities for enantioselective processes. With a few notable exceptions, metal-organic assemblies have not been explored for chirotechnology. [8, 9] Herein, we report the efficient self-assembly of a chiral porous macromolecule from the semiflexible pyridyl-functionalized metallosalen [ZnL] using coordination bonds (Figure 1).[6a] Single crystals of the robust metallomacrocycle show a reversibly and controllably dynamic behavior induced by external stimuli, and remarkably, can be used to separate small racemic alcohols with an enantioselectivity of up to 99.8 % ee.Heating Zn(NO 3 ) 2 ·6 H 2 O and H 2 L (1:1) in a mixture of DMF and CH 3 CN afforded light-yellow, rod-like crystals in high yield. The product is stable in air and insoluble in water and common organic solvents, and was formulated as [Zn 4 L 4 ]·4 CH 3 CN (1·4 CH 3 CN) on the basis of elemental analysis, IR spectroscopy, and thermogravimetric analysis (TGA).A single-crystal X-ray diffraction study performed on 1·4 CH 3 CN reveals a metallomacrocycle constructed from four [ZnL] molecules by the complementary coordination of the pyridyl groups to the metal centers (Figure 1).[10] Compound 1·4 CH 3 CN crystallizes in the tetragonal chiral space group P4 2 , with a crystallographic C 2 axis passing through the center; thus, half of the tetramer is in the asymmetric unit. Each Zn center adopts a square-pyramidal geometry with the

Photoswitchable reagents are powerful tools for high-precision studies in cell biology. When these reagents are globally administered yet locally photoactivated in two-dimensional (2D) cell cultures, they can exert micron-and millisecond-scale biological control. This gives them great potential for use in biologically more relevant three-dimensional (3D) models and in vivo, particularly for studying systems with inherent spatiotemporal complexity, such as the cytoskeleton. However, due to a combination of photoswitch isomerization under typical imaging conditions, metabolic liabilities, and insufficient water solubility at effective concentrations, the in vivo potential of photoswitchable reagents addressing cytosolic protein targets remains largely unrealized. Here, we optimized the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based on the styrylbenzothiazole (SBT) scaffold that are nonresponsive to typical fluorescent protein imaging wavelengths and so enable multichannel imaging studies. We applied these reagents both to 3D organoids and tissue explants and to classic model organisms (zebrafish, clawed frog) in one-and two-protein imaging experiments, in which spatiotemporally localized illuminations allowed them to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in vivo with cellular precision and second-level resolution. These nanomolar, in vivo capable photoswitchable reagents should open up new dimensions for high-precision cytoskeleton research in cargo transport, cell motility, cell division, and development. More broadly, their design can also inspire similarly capable optical reagents for a range of cytosolic protein targets, thus bringing in vivo photopharmacology one step closer to general realization.

Photoswitchable reagents to modulate microtubule stability and dynamics are an exciting tool approach towards micron- and millisecond-scale control over endogenous cytoskeleton-dependent processes. When these reagents are globally administered yet locally photoactivated in 2D cell culture, they can exert precise biological control that would have great potential for in vivo translation across a variety of research fields and for all eukaryotes. However, photopharmacology's reliance on the azobenzene photoswitch scaffold has been accompanied by a failure to translate this temporally- and cellularly-resolved control to 3D models or to in vivo applications in multi-organ animals, which we attribute substantially to the metabolic liabilities of azobenzenes. Here, we optimised the potency and solubility of metabolically stable, druglike colchicinoid microtubule inhibitors based instead on the styrylbenzothiazole (SBT) photoswitch scaffold, that are non-responsive to the major fluorescent protein imaging channels and so enable multiplexed imaging studies. We applied these reagents to 3D systems (organoids, tissue explants) and classic model organisms (zebrafish, clawed frog) with one- and two-protein imaging experiments. We successfully used systemic treatment plus spatiotemporally-localised illuminations in vivo to photocontrol microtubule dynamics, network architecture, and microtubule-dependent processes in these systems with cellular precision and second-level resolution. These nanomolar, in vivo-capable photoswitchable reagents can prove a game-changer for high-precision cytoskeleton research in cargo transport, cell motility, cell division and development. More broadly, their straightforward design can also inspire the development of similarly capable optical reagents for a range of protein targets, so bringing general in vivo photopharmacology one step closer to productive realisation.